Synthesis of [1‐11C]ethyl iodide from [11C]carbon monoxide and its application in alkylation reactions

A method is presented for preparing [1‐¹¹C]ethyl iodide from [¹¹C]carbon monoxide. The method utilizes methyl iodide and [¹¹C]carbon monoxide in a palladium‐mediated carbonylation reaction to form a mixture of [1‐¹¹C]acetic acid and [1‐¹¹C]methyl acetate. The acetates are reduced to [1‐¹¹C]ethanol and subsequently converted to [1‐¹¹C]ethyl iodide. The synthesis time was 20 min and the decay‐corrected radiochemical yield of [1‐¹¹C]ethyl iodide was 55 ± 5%. The position of the label was confirmed by ¹³C‐labelling and ¹³C‐NMR analysis. [1‐¹¹C]Ethyl iodide was used in two model reactions, an O‐alkylation and an N‐alkylation. Starting with approximately 2.5 GBq of [¹¹C]carbon monoxide, the isolated decay‐corrected radiochemical yields for the ester and the amine derivatives were 45 ± 0.5% and 25 ± 2%, respectively, based on [¹¹C]carbon monoxide. Starting with 10 GBq of [¹¹C]carbon monoxide, 0.55 GBq of the labelled ester was isolated within 40 min with a specific radioactivity of 36 GBq/µmol. Copyright © 2004 John Wiley & Sons, Ltd.     

Synthesis of [1‐11C]propyl and [1‐11C]butyl iodide from [11C]carbon monoxide and their use in alkylation reactions

A method to prepare [1‐¹¹C]propyl iodide and [1‐¹¹C]butyl iodide from [¹¹C]carbon monoxide via a three step reaction sequence is presented. Palladium mediated formylation of ethene with [¹¹C]carbon monoxide and hydrogen gave [1‐¹¹C]propionaldehyde and [1‐¹¹C]propionic acid. The carbonylation products were reduced and subsequently converted to [1‐¹¹C]propyl iodide. Labelled propyl iodide was obtained in 58±4% decay corrected radiochemical yield and with a specific radioactivity of 270±33 GBq/µmol within 15 min from approximately 12 GBq of [¹¹C]carbon monoxide. The position of the label was confirmed by ¹³C‐labelling and ¹³C‐NMR analysis. [1‐¹¹C]Butyl iodide was obtained correspondingly from propene and approximately 8 GBq of [¹¹C]carbon monoxide, in 34±2% decay corrected radiochemical yield and with a specific radioactivity of 146±20 GBq/µmol. The alkyl iodides were used in model reactions to synthesize [O‐propyl‐1‐¹¹C]propyl and [O‐butyl‐1‐¹¹C]butyl benzoate. Propyl and butyl analogues of etomidate, a β‐11‐hydroxylase inhibitor, were also synthesized. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis of [11C‐carbonyl]hydroxyureas by a rhodium‐mediated carbonylation reaction using [11C]carbon monoxide

[¹¹C]Hydroxyurea has been successfully labelled using [¹¹C]carbon monoxide at low concentration. The decay‐corrected radiochemical yield was 38±3%, and the trapping efficiency of [¹¹C]carbon monoxide in the order of 90±5%. This synthesis was performed by a rhodium‐mediated carbonylation reaction starting with azidotrimethylsilane and the rhodium complex being made in situ by chloro(1,5‐cyclooctadiene)rhodium(I) dimer ([Rh(cod)Cl]₂) and 1,2‐bis(diphenylphosphino)ethane (dppe). (¹³C)Hydroxyurea was synthesized using this method and the position of the labelling was confirmed by ¹³C‐NMR. In order to perform accurate LC–MS identification, the derivative 1‐hydroxy‐3‐phenyl[¹¹C]urea was synthesized in a 35±4% decay‐corrected radiochemical yield. After 13 µA h bombardment and 21 min synthesis, 1.6 GBq of pure 1‐hydroxy‐3‐phenyl[¹¹C]urea was collected starting from 6.75 GBq of [¹¹C]carbon monoxide and the specific radioactivity of this compound was in the order of 686 GBq/µmol (3.47 nmol total mass). [¹¹C]Hydroxyurea could be used in conjunction with PET to evaluate the uptake of this anticancer agent into tumour tissue in individual patients. Copyright © 2006 John Wiley & Sons, Ltd.     

[carbonyl‐11C]Benzyl acetate: Automated radiosynthesis via Pd‐mediated [11C]carbon monoxide chemistry and PET measurement of brain uptake in monkey

[carbonyl‐¹¹C]Benzyl acetate ([¹¹C]1) has been proposed as a potential agent for imaging glial metabolism of acetate to glutamate and glutamine with positron emission tomography. [¹¹C]1 was synthesized from [¹¹C]carbon monoxide, iodomethane and benzyl alcohol via palladium‐mediated chemistry. The radiosynthesis was automated with a modified Synthia platform controlled with in‐house developed Labview software. Under production conditions, [¹¹C]1 was obtained in 10% (n=6) decay‐corrected radiochemical yield from [¹¹C]carbon monoxide in >96% radiochemical purity and with an average specific radioactivity of 2415 mCi/µmol. The total radiosynthesis time was about 45 min. Peak uptake of radioactivity in monkey brain (SUV=3.1) was relatively high and may be amenable to measuring uptake and metabolism of acetate in glial cells of the brain. Published in 2010 by John Wiley & Sons, Ltd.     

[11C]Methanol production by a fast and mild aqueous‐phase reduction of [11C]formic acid with samarium diiodide

The reduction of [¹¹C]carbon dioxide to [¹¹C]methanol with lithium aluminium hydride (LiAlH₄) and subsequent conversion into [¹¹C]methyl iodide is a standard way of producing the latter precursor for radiolabelling. However, it suffers from appreciable losses by incomplete reduction giving [¹¹C]formate. We show that samarium diiodide (SmI₂) can be used to improve the yield of [¹¹C]methanol by its ability to efficiently reduce [¹¹C]formate to [¹¹C]methanol. This can be done either by making [¹¹C]formate intentionally and treating it with SmI₂ or by treating the LiAlH₄‐reduced [¹¹C]CO₂ with SmI₂. In the latter approach, sodium thiosulphate has a similar effect as SmI₂. Hydriodic acid was also shown to exert some reducing action on [¹¹C]formate too. [¹¹C]Carbonate is reduced to a small extent by SmI₂ under the mild conditions employed. In contrast to the very easy [¹¹C]formate reduction, SmI₂ had little effect on [¹¹C]acetate and practically no [¹¹C]ethanol could be produced. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis of diethyl [carbonyl‐11C]malonate from [11C]carbon monoxide by rhodium‐promoted carbonylation and its application as a reaction intermediate

Rhodium‐mediated carbonylation reaction was applied to synthesize diethyl [carbonyl‐¹¹C]malonate using [¹¹C]carbon monoxide at low concentration. The synthesis was performed starting with ethyl diazoacetate, ethanol and the rhodium complex being made in situ by chloro(1,5‐cyclooctadiene)rhodium(I) dimer ([Rh(cod)Cl]₂) and 1,2‐bis(diphenylphosphino)ethane (dppe), and the reaction is assumed to proceed via a ketene intermediate. The isolated radiochemical yield was 20% (75% analytical radiochemical yield) and the trapping efficiency of [¹¹C]carbon monoxide in the order of 85%. The specific radioactivity of this compound was measured at 127 GBq/µmol (7.28 nmol total mass) after 8 µAh bombardment and 35 min synthesis. The corresponding ¹³C‐labelled compound was synthesized using (¹³C)carbon monoxide to confirm the position of the carbonyl‐labelled atom by ¹³C‐NMR. Diethyl [carbonyl‐¹¹C]malonate was further used in subsequent alkylation step using ethyl iodide and tetrabutylammonium fluoride to obtain diethyl diethyl [carbonyl‐¹¹C]malonate in 50% analytical radiochemical yield. Copyright © 2006 John Wiley & Sons, Ltd.     

A convenient synthesis of [11C]paraquat and other [N‐methyl‐11C]bisquaternary ammonium compounds

[¹¹C]Paraquat was synthesized by the reaction of [¹¹C]methyl triflate with the mono‐triflate salt of 1‐methyl‐[4,4′]bipyridinyl. The product was selectively separated from the precursor by a microcolumn of Chelex 100 ion exchange resin. The method was applied to the synthesis of a variety of [N‐methyl‐¹¹C]bisquaternary ammonium compounds. This is the first reported use of a chelating cation exchange resin for the selective purification of organic dications. Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis of no‐carrier‐added [11C]methanesulfonyl chloride as a new labeling agent for PET radiopharmaceutical development

Three methods are described for labeling methanesulfonyl (mesyl) chloride with no‐carrier‐added (NCA) carbon‐11 (t_1/2=20.4 min; β⁺=99.8%) to provide a new labeling agent of potential value in radiopharmaceutical development for positron emission tomography (PET). Each method uses NCA [¹¹C]iodomethane, which is readily prepared from cyclotron‐produced [¹¹C]carbon dioxide or [¹¹C]methane by known procedures. The first method (route 1) consisted of converting [¹¹C]iodomethane into [¹¹C]methyllithium and then treatment with sulfuryl chloride. NCA [¹¹C]mesyl chloride was obtained in 78% decay‐corrected radiochemical yield (RCY) from [¹¹C]iodomethane at 30 min from the end of radionuclide production (ERP). However, co‐production of n‐butanesulfonyl chloride limited the extent of reaction of this labeling agent with 1,2,3,4‐tetrahydroisoquinoline (THIQ). Two new syntheses were devised, based on converting [¹¹C]iodomethane into [¹¹C]methanethiol by passage over heated sodium hydrogen sulfide for subsequent treatment with either chlorinated water (route 2) or over heated manganese(IV) oxide and then calcium hypochlorite (route 3). These procedures gave NCA [¹¹C]mesyl chloride in 77% (route 2) and 28% (route 3) RCYs from [¹¹C]iodomethane at about 20 min from ERP. Crude [¹¹C]mesyl chloride, produced by route 2 or 3, reacted rapidly with THIQ to give the corresponding NCA [¹¹C]methanesulfonamide in 49 or 74% RCY, respectively. Phenol was also converted rapidly with [¹¹C]mesyl chloride into the corresponding [¹¹C]mesylate (>90% RCY). Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis of N‐(2,5‐dimethoxybenzyl)‐N‐(5‐fluoro‐2‐phenoxyphenyl)[carbonyl‐11C]acetamide ([carbonyl‐11C]DAA1106) and analogues using [11C]carbon monoxide and palladium(0) complex

N‐(2,5‐Dimethoxybenzyl)‐N‐(5‐fluoro‐2‐phenoxyphenyl)acetamide (DAA1106), a potent and selective ligand for peripheral benzodiazepine receptor, and eight structurally related analogues were labelled with ¹¹C at the carbonyl position using a low concentration of [¹¹C]carbon monoxide and the micro‐autoclave technique. A combinatorial approach was applied to synthesize the analogues using similar reaction conditions. Palladium‐mediated carbonylation using tetrakis(triphenylphosphine)palladium, various amines and methyl iodide or iodobenzene was employed in the synthesis. The ¹¹C‐labelled products were obtained with 10–55% decay‐corrected radiochemical yields and the final product was more than 97% pure in all cases. Specific radioactivity was determined for the compound [carbonyl‐¹¹C]DAA1106 using a single experiment and a 10‐µA h bombardment. The specific radioactivity, measured 36 min after end of bombardment, was 455 GBq/µmol. Synthetic routes to the precursors and reference compounds were also developed. The presented approach is a novel method for the synthesis of [carbonyl‐¹¹C]DAA1106 and its analogues, and allows the formation of a library of ¹¹C‐labelled DAA1106 analogues which can be used to optimize the performance as a potential positron emission tomography tracer. Copyright © 2007 John Wiley & Sons, Ltd.     

Reduction of [11C]CO2 to [11C]CO using solid supported zinc

A new method for the reduction of no‐carrier‐added [¹¹C]carbon dioxide into [¹¹C]carbon monoxide ([¹¹C]CO) is described, in which the reductant (zinc) is supported on fused silica particles. Using this setup, which allows for a reduction temperature (485°C) well above the melting point for zinc (420°C), radiochemical yields of up to 96% (decay‐corrected) were obtained. A slight decrease in radiochemical yield was observed upon repeated [¹¹C]CO productions (93 ± 3%, n  = 20). The methodology is convenient and efficient and provides a straightforward path to no‐carrier‐added production of [¹¹C]CO.     

High-yielding,automated radiosynthesis of [11C]martinostat using [11C]methyl triflate

Histone deacetylases (HDACs) mediate epigenetic mechanisms implicated in a broad range of central nervous system dysfunction, including neurodegenerative diseases and neuropsychiatric disorders. [¹¹C]Martinostat allows in vivo quantification of class I/IIb HDACs and may be useful for the quantification of drug–occupancy relationship, facilitating drug development for disease modifying therapies. The present study reports a radiosynthesis of [¹¹C]martinostat using [¹¹C]methyl triflate in ethanol, as opposed to the originally described synthesis using [¹¹C]methyl iodide and DMSO. [¹¹C]Methyl triflate is trapped in a solution of 2 mg of precursor 1 dissolved in anhydrous ethanol (400 μl), reacted at ambient temperature for 5 min and purified by high-performance liquid chromatography; 1.5–1.8 GBq (41–48 mCi; n = 3) of formulated [¹¹C]martinostat was obtained from solid-phase extraction using a hydrophilic–lipophilic cartridge in a radiochemical yield of 11.4% ± 1.1% (nondecay corrected to trapped [¹¹C]MeI), with a molar activity of 369 ± 53 GBq/μmol (9.97 ± 1.3 Ci/μmol) at the end of synthesis (40 min) and validated for human use. This methodology was used at our production site to produce [¹¹C]martinostat in sufficient quantities of activity to scan humans, including losses incurred from decay during pre-release quality control testing.     

[11C]methyl iodide from [11C]methane and iodine using a non‐thermal plasma method

A method and an apparatus for preparing [¹¹C]methyl iodide from [¹¹C]methane and iodine in a single pass through a non‐thermal plasma reactor has been developed. The plasma was created by applying high voltage (400 V/31 kHz) to electrodes in a stream of helium gas at reduced pressure. The [¹¹C]methane used in the experiments was produced from [¹¹C]carbon dioxide via reduction with hydrogen over nickel. [¹¹C]methyl iodide was obtained with a specific radioactivity of 412 ± 32 GBq/µmol within 6 min from approximately 24 GBq of [¹¹C]carbon dioxide. The decay corrected radiochemical yield was 13 ± 3% based on [¹¹C]carbon dioxide at start of synthesis. [¹¹C]Flumazenil was synthesized via a N‐alkylation with the prepared [¹¹C]methyl iodide. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis of a delta opioid agonist in [2H6], [2H4], [11C], and [14C] labeled forms

In support of a program to develop a treatment for depression, four labeled forms of a delta opioid agonist were prepared. The [²H₄] labeled form was prepared using a relatively straightforward conversion of [²H₄]bromoethanol to [²H₄]N‐methyl‐2‐hydroxyethylamine. The key step in the synthesis of the [²H₆] labeled form involved the Pd‐catalyzed exchange in D₂O of 8‐quinolin‐8‐ol to give [²H₆] 8‐quinolin‐8‐ol. The C‐14 labeled form was synthesized in one step using [¹⁴C]carbonylation, and the C‐11 labeled form was prepared in two steps from ¹¹CH₃I. Copyright © 2011 John Wiley & Sons, Ltd.     

One‐pot synthesis of [11C]ureas via triphenylphosphinimines

A series of ¹¹C‐labeled ureas was prepared using a rapid and efficient one‐pot procedure. First, the intermediate [¹¹C]phenylisocyanate was formed with phenyltriphenylphosphinimine and [¹¹C]CO₂. A range of amines was then reacted with the [¹¹C]phenylisocyanate yielding the [¹¹C]urea derivatives in short synthesis times. This easy‐to‐handle method circumvents disadvantages of known procedures and generates the possibility to prepare other kinds of ¹¹C‐labeled compounds using a variety of phenylphosphinimines in combination with different nucleophiles. The presented approach is an alternative to the use of established methods in ¹¹C‐labeling chemistry. Copyright © 2006 John Wiley & Sons, Ltd.     

A convenient method to produce [14C]carbon monoxide and its application to the radiosynthesis of [carboxyl‐14C]celivarone, [carboxyl‐14C]SSR149744

[carboxyl‐¹⁴C]Celivarone was synthesised from barium [¹⁴C]carbonate with overall radiochemical yields in the range 49–53%. The synthetic route involves [¹⁴C]carbonylation methodology, which both decreased the number of synthetic steps and increased the yields obtained from previous synthetic routes.     

Radiosynthesis of [N‐methyl‐11C]methylene blue

In this paper we present the radiochemical synthesis of the novel compound [N‐methyl‐¹¹C]methylene blue. The synthesis of [N‐methyl‐¹¹C]methylene blue was accomplished by means of ¹¹C‐methylation of commercially available Azure B using [¹¹C]methyl trifluoromethanesulfonate ([¹¹C]methyl triflate). Following purification [N‐methyl‐¹¹C]methylene blue was obtained with a radiochemical purity greater than 97% in a 4–6% decay corrected radiochemical yield. The synthesis was completed in an average of 35 min following the end of bombardment. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis of substituted [11C]ureas and [11C]sulphonylureas by Rh(I)‐mediated carbonylation

The urea moiety is present in many biologically active compounds and thus an attractive target for ¹¹C‐labelling. To extend the scope of the rhodium(I)‐mediated carbonylative cross‐coupling reaction between an azide and an amine and investigate its tolerance for functional groups, we have synthesized eight ureas and two sulphonylureas that were ¹¹C‐labelled in the carbonyl position. The decay‐corrected analytical radiochemical yields were in the range of 14–96% (from [¹¹C]carbon monoxide). For example: starting from 1.33 GBq [¹¹C]carbon monoxide, 0.237 GBq (66%) of the cytotoxic sulphonylurea [¹¹C]LY‐181984 11 was isolated within 60 min from end of bombardment. The mild reaction conditions and generality regarding functional groups of this method make it an attractive alternative to the [¹¹C]phosgene method for the synthesis of ¹¹C‐labelled ureas. Copyright © 2010 John Wiley & Sons, Ltd.     

Radiosynthesis of a 2‐substituted 4,5‐dihydro‐1H‐[2‐11C] imidazole: the I2 imidazoline receptor ligand [11C] benazoline

Benazoline (2‐naphthalen‐2‐yl‐4,5‐dihydro‐1H‐imidazole) is a selective high‐affinity ligand for the imidazoline I₂ receptor. This compound was labelled with carbon‐11 (T_1/2=20.4 min) at the number two carbon atom of its 2‐imidazoline ring. Cyclotron‐produced [¹¹C]carbon dioxide reacted with 2‐naphthylmagnesium bromide to give 2‐[carboxyl‐¹¹C]naphthoic acid in 60% radiochemical yield. The latter was heated with a mixture of ethylenediamine and its dihydrochloride at 300°C to give [¹¹C]benazoline in 16% overall yield, relative to [¹¹C]carbon dioxide and with a specific radioactivity of 54 GBq/μmol, decay corrected for end of irradiation. The procedure requires about 45 min from end of cyclotron irradiation. This method should be extendable to other imidazolines. Copyright © 2003 John Wiley & Sons, Ltd.     

Radiosynthesis of [11C]docetaxel

Docetaxel (Taxotere®) is an accepted chemotherapeutic agent for the treatment of breast cancer and non‐small cell lung cancers. A potential means of predicting response is measuring tumor uptake of [¹¹C]docetaxel using Positron Emission Tomography (PET). The synthetic approach to introduce the ¹¹C isotope in the 2‐benzoyl moiety of docetaxel unfortunately was unsuccessful. The radiosynthesis of [¹¹C]docetaxel ( 6b , Scheme 1), with the ¹¹C isotope in the BOC moiety, was however, successful using a second synthetic approach. It started with the reaction of [¹¹C]tert‐butanol with 1,2,2,2‐tetrachloroethyl chloroformate to give [¹¹C]tert‐butyl‐l,2,2,2‐tetrachloroethyl carbonate in a good overall yield (62±9%). In the final step, the [¹¹C]tert‐butoxycarbonylation of the free amine of docetaxel gave [¹¹C]docetaxel 6b in a satisfactory decay corrected yield of 10±1% (from [¹¹C]CO₂). Copyright © 2004 John Wiley & Sons, Ltd.     

Synthesis and biological evaluation of [carboxyl‐11C]eprosartan

Essential hypertension occurs in approximately 25% of the adult population and one cause of hypertension is primary aldosteronism. Targeting the angiotensin II AT₁ receptor using PET and an appropriate tracer may offer a diagnostic method for adrenocortical tissue. This report describes the synthesis of the selective AT₁ receptor antagonist [carboxyl‐¹¹C]eprosartan 10, 4‐[2‐butyl‐5‐((E)‐2‐carboxy‐3‐thiophen‐2‐yl‐propenyl)‐imidazol‐1‐ylmethyl]‐[carboxyl‐¹¹C]benzoic acid, and its precursor (E)‐3‐[2‐butyl‐3‐(4‐iodo‐benzyl)‐3H‐imidazol‐4‐yl]‐2‐thiophen‐2‐ylmethyl‐acrylic acid 9. ¹¹C‐carboxylation of the iodobenzyl moiety was performed using a palladium‐mediated reaction with [¹¹C]carbon monoxide in the presence of tetra‐n‐butyl‐ammonium hydroxide in a micro‐autoclave using a temperature gradient from 25 to 140°C over 5 min. After purification by semipreparative HPLC, [carboxyl‐¹¹C]eprosartan 10 was obtained in 37–54% decay‐corrected radiochemical yield (from [¹¹C]carbon monoxide) with a radiochemical purity >95% within 35 min of the end of bombardment (EOB). A 5‐µAh bombardment gave 2.04 GBq of 10 (50% rcy from [¹¹C]carbon monoxide) with a specific activity of 160 GBq µmol^?1 at 34 min after EOB. Frozen‐section autoradiography shows specific binding in kidney, lung and adrenal cortex. In vivo experiments in rats demonstrate a high accumulation in kidney, liver and intestinal wall. Copyright © 2009 John Wiley & Sons, Ltd.